Out of the loop: Augmenting diuresis with SGLT2 inhibitors in HF
SGLT2 inhibitors were first approved in 2013 for the treatment of type 2 diabetes. These agents act by blocking glucose and sodium reabsorption, thereby increasing glucose excretion. Glycosuria develops once blood glucose concentrations exceed 180 mg/dL, and SGLT2 receptors are responsible for 90% of glucose reabsorption in the proximal tubule of the nephron. Diabetes, hypertension, hyperlipidemia and obesity are closely linked to the development of CVD and HF. Furthermore, some antihyperglycemic agents — for example, thiazolidinediones — may worsen HF and complicate the treatment of patients with type 2 diabetes and HF.
Since 2008 and 2012, respectively, the FDA and the European Medicines Agency have mandated CV outcome trials for all new antihyperglycemic drugs approved for type 2 diabetes management. Three SGLT2 inhibitors (Table 1) — empagliflozin (Jardiance, Boehringer Ingelheim), canagliflozin (Invokana, Janssen) and, recently, dapagliflozin (Farxiga, AstraZeneca) — have demonstrated a reduction in major adverse CV events and also hospitalization for HF compared with placebo in patients with type 2 diabetes with or at high risk for CVD (Table 2).
CV outcome trials
The EMPA-REG OUTCOME trial was a large randomized study that added empagliflozin to standard of care in patients with type 2 diabetes and established atherosclerotic CVD. Pooled doses of empagliflozin demonstrated a 14% reduction in the primary outcome of major adverse CV events, defined as the composite of death from CV causes, nonfatal MI or nonfatal stroke. There was also a 38% reduction in risk for CV death and 35% reduction in HF hospitalization for patients randomly assigned to the empagliflozin treatment arm.
A subgroup analysis of 706 patients with HF were enrolled in the EMPA-REG OUTCOME trial. Use of background guideline-directed medical therapy in this population included ACE inhibitors/angiotensin receptor blockers (81%), beta-blockers (65%), diuretics (43%) and mineral corticoid receptor antagonists (6%). Patients treated with empagliflozin demonstrated a 34% reduction in the composite outcome of HF hospitalization or CV death and a 39% reduction in hospitalization/death from HF. This trial was the first to demonstrate morbidity and mortality benefits of any glucose-lowering agent in patients with type 2 diabetes and HF.
The CANVAS Program integrated data from two large randomized trials, the CANVAS and CANVAS-R studies, which compared canagliflozin with placebo. Both trials enrolled participants with type 2 diabetes and CV risk factors. Approximately 65% of patients reported a history of CVD at baseline. The primary composite outcome of major adverse CV events was 14% lower in the canagliflozin group.
Fourteen percent of patients enrolled in the CANVAS trial also reported a history of HF at baseline. The majority of patients with HF were on background therapy with a diuretic (60.1%), renin-angiotensin-aldosterone system (RAAS) blocker (85.7%) and beta-blocker (70.4%). Patients in the canagliflozin group had a 22% reduction in the composite outcome of CV death or HF hospitalization. There was also a statistically significant reduction in HF hospitalization/death and HF hospitalization alone in patients treated with canagliflozin.
The DECLARE-TIMI 58 trial is the largest to date and included patients with type 2 diabetes at high risk for CVD who were randomly assigned to dapagliflozin or placebo. Approximately 40% of patients had established ASCVD.
The coprimary efficacy outcomes were major adverse CV events and the composite of CV death or HF hospitalization. Patients randomly assigned to the dapagliflozin group met noninferiority, however it was not found to be superior to placebo for major adverse CV events. The dapagliflozin group demonstrated superiority to placebo with regard to the composite endpoint of CV death or HF hospitalization, which was largely driven by a reduction in HF hospitalization.
Recently, data were analyzed for the patients with HF enrolled in DECLARE-TIMI 58. Approximately 671 patients (3.9%) enrolled had HFrEF (defined as EF < 45%) and were treated with ACE inhibitors/angiotensin receptor blockers (86%), beta-blockers (80.7%), diuretics (66.9%) and mineralocorticoid receptor antagonists (30.3%). Interestingly, dapagliflozin was found to reduce the risk for CV death or HF hospitalization to a greater degree in patients with HFrEF compared with those without it.
The CVD-REAL trial was a large retrospective, propensity-matched study that used claims data from six different countries to identify 309,056 patients with type 2 diabetes who were newly started on a SGLT2 inhibitor (canagliflozin, dapagliflozin or empagliflozin) compared with other glucose-lowering agents. Approximately half of the patients were men (mean age, 57 years). CV therapies at baseline included antihypertensive agents (80%), statins (67.4%) and loop diuretics (9.3%). In contrast to the safety and efficacy CV outcome trials, 87% of the patient cohort did not have a history of CVD and only 3.1% had a history of HF at baseline.
Patients who were newly initiated on a SGLT2 inhibitor had a 39% lower risk for the primary outcome of HF hospitalization, compared with those started on another glucose-lowering agent. Most patients were prescribed canagliflozin (53%), followed by dapagliflozin (42%) and empagliflozin (5%). Secondary outcomes, including all-cause death and a composite of HF hospitalization or all-cause death, were significantly reduced for patients who received treatment with an SGLT2 inhibitor. The mean follow-up period for all three outcomes between the two groups ranged from 211 to 271 days. Data from this trial suggest the beneficial effects of SGLT2 inhibitors likely span the drug class and may be extended to patients with type 2 diabetes at low CV risk.
Clinical implications in HF
The previously reviewed CV outcome trials demonstrated the benefit of SGLT2 inhibitors on the reduction of major adverse CV events in patients with type 2 diabetes, despite subtle differences between the trials. The EMPA-REG OUTCOME trial enrolled only patients with established ASCVD, whereas the CANVAS and DECLARE-TIMI 58 trials enrolled a mix of patients with established or at high risk for ASCVD. Background medical therapies with RAAS inhibitors were similar among the trials, but the use of beta-blockers and diuretics varied. Furthermore, 10% to 14% of patients enrolled in the SGLT2 inhibitor CV outcome trials had HF at baseline. Among all three trials, the identification of HF at baseline was investigator-reported and not based on consistent diagnostic criteria. Therefore, it is unknown if the majority of patients with HF had preserved or reduced ejection fraction.
The impact of SGLT2 inhibitors on HF outcomes from current CV outcome trials is likely not driven by the small reduction in HbA1c (mean reduction, 0.4% to 0.6%). The EMPA-REG OUTCOME investigators attributed the early divergence for the composite outcome of HF hospitalization or CV death between empagliflozin and placebo treatment groups to the unique drug properties: osmotic diuresis, effects on plasma volume and sodium retention.
Other potential benefits of SGLT2 inhibitors include reduced BP, arterial stiffness and weight without increased heart rate. Weight loss (average BMI, 1-2 kg/m2) and reduction in systolic BP (average, 3-6 mm Hg) may be attributed to the natriuretic effects of SGLT2 inhibitors. The direct mechanism of SGLT2 inhibitors on the CV system, arterial stiffness and cardiorenal benefits has yet to be elucidated, however murine and human models have demonstrated the potential for improving diastolic dysfunction. For these reasons, SGLT2 inhibitors may benefit the HF population, particularly HFpEF, as those patients frequently also have comorbid conditions, such as obesity, hypertension and diabetes.
There are two ongoing phase 3 clinical trials, EMPEROR-Reduced and EMPEROR-Preserved, which compare empagliflozin with placebo in patients with HFrEF or HFpEF, in the absence of type 2 diabetes. Both trials are currently recruiting patients to evaluate the effect of empagliflozin on the composite primary outcome of CV death or adjudicated HF hospitalization. EMPEROR-Reduced will add empagliflozin to guideline-directed medical therapy for those patients with a left ventricular EF of 40% or less. Both trials anticipate completion in June 2020.
The SGLT2 inhibitor CV outcome trials directly influenced the 2019 American Diabetes Association (ADA) pharmacologic recommendation to consider the addition of an SGLT2 inhibitor to metformin for patients with type 2 diabetes and established ASCVD at high risk for HF. If a patient with type 2 diabetes and HF is unable to take an SGLT2 inhibitor, then a GLP-1 receptor agonist may be considered. Certain GLP-1 receptor agonists, specifically liraglutide (Victoza, Novo Nordisk), have demonstrated benefit with regard to the reduction of major adverse CV events, however none of these agents have been successful in reducing HF events.
The ADA endorses empagliflozin and canagliflozin, however the CV benefits of these agents are thought to be a drug-class effect and are likely independent of dose. Empagliflozin and canagliflozin carry an FDA indication for CV reduction in the setting of type 2 diabetes, but are not indicated for use in patients without diabetes. The FDA may expand use of SGLT2 inhibitors in patients with HF without type 2 diabetes, pending favorable results of ongoing trials, potentially increasing access and patient assistant programs for this drug class.n
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- For more information:
- Megan Valente, PharmD, BCACP, is a heart failure pharmacy clinical specialist in the department of pharmacy at The MetroHealth System.
- Kathleen D. Faulkenberg, PharmD, BCPS, is a heart failure and heart transplant clinical pharmacist in the department of pharmacy at Cleveland Clinic.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice, School of Pharmacy and Pharmaceutical Sciences, Binghamton University. She can be reached at firstname.lastname@example.org.
Disclosures: The authors report no relevant financial disclosures.